Glucosylceramide synthase-IN-3 (compound BZ1) is a highly potent, brain-penetrant, and orally active inhibitor of glucosylceramide synthase (GCS), exhibiting an IC50 value of 16 nM for human GCS. This compound, designated as Glucosylceramide synthase-IN-3, finds potential applications in Gaucher's disease research [1] [2].

Glucosylceramide synthase-IN-2 (compound BZ1) causes measuring the reduction of glucosylceramide and the cellular IC50 was determined to be 94 nM in human and 160 nM in mouse with cellular activity was confirmed using a fibroblast assay [1]. Glucosylceramide synthase-IN-2 has the IC50 of 20 nM in primary neurons [1]. Glucosylceramide synthase-IN-2 (10, 30, 100, 300 nM) produces a dose-dependent reduction in glycosphingolipids in WT and D409V mouse cortical neurons. Glucosylceramide synthase-IN-2 decreases the amount of detergent-insoluble pS129 α-syn [1].

Eight hours after a single dose of Glucosylceramide synthase-IN-2 (compound BZ1; 6, 20 or 100 mg/kg; oral gavage; formulated in 30% captisol), plasma GlcCer C:16:0 is reduced in a dose-dependent fashion up to ~75% of concentration in vehicle treated animals. Brain GlcCer is also significantly reduced to concentrations of ~48% of vehicle treated controls in C57BL6 mice (8 weeks of age, male) [1]. Glucosylceramide synthase-IN-2 (6, 20 or 100 mg/kg/day for 4 days; oral gavage) causes larger reductions in GlcCer [1]. Glucosylceramide synthase-IN-2 has good pharmaceutical properties with high permeability (pApp=26.54) and is not a substrate of P-gp [1].